Bottom Line:
To better understand its natural history, we undertook a detailed examination of 197 autopsies performed on women who died of breast cancer.Genomic analysis revealed DNA copy number variation between the primary tumour and metastases (e.g. amplification of 2q11.2-q12.1 and 10q22.2-q22.3) but little variation between metastases from the same patient.In summary, the association of CNS and bone metastases, liver and gynaecological metastases in young women and the risk of liver metastases following surgery have important implications for the management of patients with breast cancer.

fig01: Clonal nature of metastatic progression. The primary breast tumour and metastases from lymph nodes (axilla and non-axillary), lung, liver and adrenal gland from autopsy case 7 were studied by aCGH. (A) Whole-genome copy number profiles were strikingly similar, indicating a close clonal relationship between tumours during progression. Individual plots for chromosomes 2 (B), 10 (C) and 17 (D) are shown for the primary breast tumour and the lung metastases, which are representative of all metastases, and DNA copy number alterations along chromosome 17 emphasize this clonal relatedness of tumours; arrow in (D) marks the amplification of HER2/ERBB2 and all tumour deposits were HER2 3+ positive (not shown). Array CGH also detected an amplification of 2q11.2–q12.1 in the primary tumour only [arrow in (B)] and an amplification of 10q22.2–q22.3 in all metastases, but not in the primary tumour [arrow in (C)]. FISH analysis indicated that this clonal diversity occurred in the primary tumour: the 2q amplification (green) was restricted to the primary tumour (E, F), but the 10q22 amplification (red) was found in a different subclone (in a different tissue block) of the primary tumour (G, H) and was identified in all metastases (I, J) (see also supplementary material, Figure S2).

Mentions:
Most copy number alterations (CNAs; deletions, gains and amplifications) were shared between the primary tumour and its metastases, reflecting the close clonal relationship of all tumour foci within a case (Figure 1; see also supplementary material, Figures S3–S7). The majority of CNAs therefore occurred as early events in the major clonal expansion of the primary tumour. However, evidence of clonal diversity was observed between the primary tumour and its corresponding metastases in four cases. For example, in case 7, focal amplification of 2q11.2–q12.1 was detected in the primary tumour but not in the metastases, and amplification of 10q22.2–q22.3 was identified in the metastases but not in the primary tumour. FISH analysis demonstrated that this clonal heterogeneity occurred within the primary tumour (Figure 1; see also supplementary material, Figure S2) and that the clone harbouring the 10q22 amplification had spread. Similarly, in other cases, additional CNAs were detected in all the metastases compared with the corresponding primary tumour (see supplementary material, Figures S5–S7), suggesting (as for case 7) that the clonal diversity most likely occurred prior to dissemination. Of these six cases, only one patient received adjuvant chemotherapy, suggesting that the genomic heterogeneity observed was not treatment-induced.

fig01: Clonal nature of metastatic progression. The primary breast tumour and metastases from lymph nodes (axilla and non-axillary), lung, liver and adrenal gland from autopsy case 7 were studied by aCGH. (A) Whole-genome copy number profiles were strikingly similar, indicating a close clonal relationship between tumours during progression. Individual plots for chromosomes 2 (B), 10 (C) and 17 (D) are shown for the primary breast tumour and the lung metastases, which are representative of all metastases, and DNA copy number alterations along chromosome 17 emphasize this clonal relatedness of tumours; arrow in (D) marks the amplification of HER2/ERBB2 and all tumour deposits were HER2 3+ positive (not shown). Array CGH also detected an amplification of 2q11.2–q12.1 in the primary tumour only [arrow in (B)] and an amplification of 10q22.2–q22.3 in all metastases, but not in the primary tumour [arrow in (C)]. FISH analysis indicated that this clonal diversity occurred in the primary tumour: the 2q amplification (green) was restricted to the primary tumour (E, F), but the 10q22 amplification (red) was found in a different subclone (in a different tissue block) of the primary tumour (G, H) and was identified in all metastases (I, J) (see also supplementary material, Figure S2).

Mentions:
Most copy number alterations (CNAs; deletions, gains and amplifications) were shared between the primary tumour and its metastases, reflecting the close clonal relationship of all tumour foci within a case (Figure 1; see also supplementary material, Figures S3–S7). The majority of CNAs therefore occurred as early events in the major clonal expansion of the primary tumour. However, evidence of clonal diversity was observed between the primary tumour and its corresponding metastases in four cases. For example, in case 7, focal amplification of 2q11.2–q12.1 was detected in the primary tumour but not in the metastases, and amplification of 10q22.2–q22.3 was identified in the metastases but not in the primary tumour. FISH analysis demonstrated that this clonal heterogeneity occurred within the primary tumour (Figure 1; see also supplementary material, Figure S2) and that the clone harbouring the 10q22 amplification had spread. Similarly, in other cases, additional CNAs were detected in all the metastases compared with the corresponding primary tumour (see supplementary material, Figures S5–S7), suggesting (as for case 7) that the clonal diversity most likely occurred prior to dissemination. Of these six cases, only one patient received adjuvant chemotherapy, suggesting that the genomic heterogeneity observed was not treatment-induced.

Bottom Line:
To better understand its natural history, we undertook a detailed examination of 197 autopsies performed on women who died of breast cancer.Genomic analysis revealed DNA copy number variation between the primary tumour and metastases (e.g. amplification of 2q11.2-q12.1 and 10q22.2-q22.3) but little variation between metastases from the same patient.In summary, the association of CNS and bone metastases, liver and gynaecological metastases in young women and the risk of liver metastases following surgery have important implications for the management of patients with breast cancer.